Sulfur-containing benzylamino compounds



United States Patent 0 I omxcnr wherein X represents a radical selectedfrom the group consisting of S, SO and -SO and R represents hydrogen ora halogen substituent such as chloro.

My invention also includes salts of these compounds With nontoxic,pharmacologically-acceptable acids, particularly acid addition saltswith hydrohalic acids such as hydrochloric acid, and hydrobromic acid.

Among novel chemical compounds Within the scope of my invention may bementioned sulfides, and oxidation products thereof, such as:

l-benzylaminornethyl, 4-benzylthiomethylcyclohexane (Compound I)l-benzylaminomethyl, 4-benzylthiomethylcyclohexane,

S-oxide (Compound II);

1-benzylaminomethyl-4-benzylsulfonylmethylcyclohexane (Compound ill) andl-benzylthiomethyl, 4-(o-chlorobenzylaminomethyl)- cyclohexane (CompoundIV).

In the type of formula given for my novel chemical compounds, in baseform, the substituents X and R in these compounds are as follows:

Compound X R I S H -s on TTT -SO2- H IV- S C1 The hydrohalide salts,particularly the hydrochloride salts, of these compounds, as well as thebases, are characterized by possessing biological activities, which areset forth more fully below.

In preparing the new chemical compounds the following methods ofsynthesis were employed. Compound I, l-benzylaminomethyl, 4benzylthiomethylcyclohexane; arid Compound 1V, l-benzylthiomethyl,4-(o-chlorobenzylaminomethyl)-cyclohexane; may be prepared by anidentical series of reactions, using as starting materials4-aminomethylcyclohexanemethanol and either benzaldehyde oro-chlorobenzaldehyde. Thus: 4-aminomethylcyclohexanemethanol and onemolar equivalent of the appropriate benzaldehyde may be converted to thecorresponding Schiti base by refluxing in benzene. It may then bereduced to the corresponding amine derivative with sodium borohydride.The resulting 4-benzylaminomethylcyclohexanemethanol may then beconverted to the chloromethyl derivative with thionyl chloride.Condensation of the chloromethyl derivative With a-toluenethiol in thepresence of sodium hydroxide yields the benzylthiomethyl derivatives.

The benzylthiomethyl derivative when R is hydrogen (Compound I) may beoxidized with sodium metaperiodate to yield the corresponding sulfoxide(Compound 11). Oxidation of the hydrochloride salt of thebenzylthiomethyl derivative with hydrogen peroxide, followed byregeneration of the free base, results in the corresponding sulfone,Compound 111.

This sequence of chemical reactions may be indicated schematically asfollows:

NalOi I I CHgS-CE2- H2\SL 'OH2 0 Compound I: R :13: (1) H01 Compound II:R =H Compound IV: R =C1 H2 2 (3) NaOH Compound III: R=H

The new chemical compounds possess utility in the fields of cholesterollowering agents, i.e. effective to lower the levels of cholesterol inthe blood, and as antibacterial agents.

Thus, l-benzylaminomethyl, 4-benzylthiomethylcyclohexane acts to lowercholesterol levels in the rat by 27 percent at an oral dose level of 75micromoles per kilogram of rat body weight.

The compound l-benzylaminomethyl, 4-benzylsulfonylmethylcyclohexane(Ill), as well as l-benzylthiomethyl,4-(o-chlorobenzylaminomethyl)-cyciohexane (IV), are antibacterialagents. The activity of these two compounds at dilutions of 1 part ofthe compound in the specified quantity of aqueous liquid, againstvarious microorganisms is shown in the following table.

ANTIBACTERIAL ACTIVITY methylcyclohexane, S-oxide is chiefly useful asan intermediate for the production of l-benzylaminomethyl, 4-benzylsulfonylmethylcyclohexane as, by any of a number of well knownmethods, sulfoxides may be oxidized to sulfones.

The following examples illustrate my invention.

Example I l-BENZYLAMINOMETHYLCYCLOHEXANEMETHANOL4-aminomethylcyclohexanemethanol (42.9 g.) and benzaldehyde (31.8 g.)were refluxed in benzene solution until the theoretical quantity ofwater had been removed azeotropically. The resulting Schitf base, Mnax.247 m (e=*17,800), was dissolved in methanol and reduced by addingsodium borohydride (11.4 g.) portion- Wise. After refluxing for threehours, the methanol was removed in vacuo, i.e., at a pressure belowatmospheric pressure, and the residue distributed between water andether. The ether layer yielded the title product in 92% yield. It hadxmax. 259 m (e=267). The hydrochloride salt was prepared with etherealhydrogen chloride and crystallized from an isopropanolzether mixture. Ithad M.P. 160l61 C. Analysis confirmed the empiric formula C15H24NOC1.

Example 2 4-BENZYLAMINOMETHYLCYCLOHEXANE METHYLCLORIDE4-benzylaminomethylcyclohexane methanol (43.7 g.) dissolved inchloroform was treated with thionyl chloride (45 ml.). The mixture wasrefluxed for 14 hours then the chloroform and excess thionyl chloridewas removed in vacuo. The residue was crystallized from isopropanol toyield the hydrochloride salt of the title compound. It had M.P. 230-2305C. Analysis confirmed the empiric formula C 5H2 Ncl2.

The title compound was prepared from its hydrochloride salt in the usualmanner. It had xmax. 258 mp. (e=2l2).

Example 3 l-BENZYLAMINOMETHYL, 4-BENZYLTHIOMETHYL- CYCLOHEXANE (COMPOUNDI) a-toluenethiol (9.32 g.) was dissolved in 70% ethanol containingsodium hydroxide (6.16 g.). 4-benzylamino- 4methylcyclohexanemethylchloride hydrochloride (22 g.) was dissolved in1:1 ethanohwater and added dropwise to the above mixture which was thenrefluxed for 30 minutes. The ethanol was removed in vacuo and theaqueous solution extracted with benzene to yield the title compound in91% yield as an oil, )tmax. 250 m (6 805). A hydrochloride salt wasprepared in the usual manner and crystallized from methanol-ether. Ithad M.P. 188.-

190 C. Analysis confirmed the empiric formula C H NSC1.

Example 4 4- (o-CHLOROBENZYLAMINOMETHYL) -CYCLOHEXANE METHANOLo-chlorobenzaldehyde (42.3 g.) and 4-arninomethylcyclohexanemethanolwere converted to the Schiff base by refluxing in benzene until thetheoretical volume of Water had been removed azeotropically. The crudeSchiif base was converted to the title compound by sodium borohydridereduction in the usual manner. It had )\max. 265 m (e=2l4). Ahydrobromide salt was prepared and crystallized from methanol-ether. Ithad M.P. 146- 148 C. Analysis confirmed the empiric formulaC15H24NOC1BI'. 7

Example 5 4- o-CHLOROBENZYLAMINOMETHYL) -CYCLOHEXANE METHYLCHLORIDEExample 6 l-BENZYLTHIOMETHYL, 4- o-CHLOROBENZYLAMINO-METHYL)-CYCLOHEZL\NE (COMPOUND IV)4-(o-chlorobenzylaminomethyl)-cyclohexane methyl chloride (20.9 g.)dissolved in 50% ethanol (50 ml.) was added dropwise to a mixture ofbenzylmercaptan (8.03 g.) and sodium hydroxide (2.6 g.) of 50% ethanol(150 ml.). The mixture was refluxed overnight, the ethanol removed andthe residue extracted with chloroform. The chloroform solution waswashed with 5% sodium hydroxide and water then dried (Na SO to yield thetitle compound as an oil. It had bands in the infrared at 1050 cmf 1500cm. and 700 CHI-1. The hydrobromide salt was prepared and crystallizedfrom an isopropanolether mixture. It had M.P. ll41l6 C. Analysisconfirmed the empiric formula C H NClBrS.

Example 7 l-BENZYLAMINOETHYL, 4-BENZYL'IHIOMETHYLCYCLO- HEXANE,S-OXIDE(COMPOUND II) Sodium metaperiodate (2.59 g., 0.012 mole) was dissolvedin water to a final concentration of 0.5 M. The solution was cooled to 0C. and l-benzylaminomethyl, 4-benzylthiomethylcyclohexane (4.3 g., 0.011mole) dissolved in water (20 ml.) was added with stirring over a periodof 10 minutes. The mixture was stirred at 0 C. for an additional 7hours, made alkaline with aqueous sodium hydroxide and extracted withether to yield the title compound (4.0 g.) as a solid which had a strongband in the infrared at 1030 cm.- The hydrochloride salt was prepared inether and crystallized from isopropanol. It had M.P. 2l8-220 C. Analysisconfirmed the empiric formula CzzHg NSOCl.

Example 8 LBENZYLAMINOMETHYL, 4-BENZYLSULPHONYL- METHYL CYCLOHEXAW(COMPOUND III) l-benzylaminomethyl, 4-benzylthiomethyl cyclohexanehydrochloride (5.5 g.) was dissolved in glacial acetic acid. To thissolution was added 30% hydrogen peroxide (3.8 ml.) and the mixturewarmed on the steam bath for 4 hours. The acetic acid was removed invacuo and the residue distributed between chloroform and 20% sodiumhydroxide. The chloroform layer yielded the title compound, Mnax. 259 m(e=4l8). The hydrochloride salt was prepared in the usual manner andcrystallized from methanol-ether. It had M.P. 251253 C. Analysiscoufirmed the empiric formula C H NSO CI.

I claim:

1. A compound selected from the group which consists of bases of theformula embracin -Q l omxom wherein R is selected from the group ofradicals consisting of hydrogen and chlorine, and X is selected from thegroup of radicals consisting of -S, SO, and SO and acid addition saltsof said bases With hydrohalic acids selected from the group Whichconsists of hydrochloric acid and hydrobromic acid.

2. l-benzylaminomethyl, 4-ber1zylthiomethylcyclohexane.

3. l-benzylaminomethyl, ane, S-oxide.

4. l-benzylaminomethyl, clohexane.

5. l-benzylthiomethyl, yl)-cycloheXane.

6. The hydrochloride salt of l-benzylaminomethyl, 4-benzylthiomethylcyclohexane.

7. The hydrochloride salt of l-benzylaminomethyl, 4-benzylthiomethylcyclohexane, S-oXide.

8. The hydrochloride salt of l-benzylaminomethyl, 4-benzylsulphonylmethyl cyclohexane.

9. The hydrobromide salt of l-benzylthiomethyl, 4-(0- chlorobenzylaminomethyl) -cyclohexane.

4-benzylthiomethylcyclohex- 4-benzylsulphonylmethylcy-4-(o-chlorobenzylaminometh- No references cited.

1. A COMPOUND SELECTED FROM THE GROUP WHICH CONSISTS OF BASES OF THEFORMUAL